tbuckley/cabot-search huggingface dataset:
Biomarkers of response to neoadjuvant atezolizumab with gemcitabine and cisplatin in muscle-invasive bladder cancer.
Authors: Michael Lattanzi, Alexander Solovyov, Jayon Lihm, Colleen Quinlan, Karissa Whiting, Hao Li, Hikmat A. Al-Ahmadie, Min Yuen Teo, David Henry Aggen, Irina Ostrovnaya, Ashley Marie Regazzi, Marwah Jihad, Dean F. Bajorin, Arjun Vasant Balar, Amir Mortazavi, Taha Merghoub, Gopa Iyer, Jonathan E. Rosenberg, Benjamin Greenbaum, Samuel Aaron Funt
Journal: Journal of Clinical Oncology (2022)

4584 Background: We previously reported the clinical outcomes of a positive multi-center phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) plus atezolizumab (A) in patients with muscle-invasive bladder cancer (Funt, et al. JCO 2022). In this and another trial of neoadjuvant GC with pembrolizumab (Rose et al, JCO 2021), PD-L1 positivity by immunohistochemistry was not predictive of non–muscle-invasive downstaging ( &lt; pT2N0). Therefore, we investigated other pre-treatment tissue-based genomic and gene expression biomarkers of response and resistance. Methods: 36 pts had pre-treatment tissue available for genomic analysis. We performed targeted hybridization capture DNA sequencing using the CLIA-certified MSK-IMPACT platform and whole transcriptome RNA sequencing. We examined genomic and gene expression biomarkers which have been previously investigated in the context of neoadjuvant cisplatin-based chemotherapy or anti-PD-1/L1 immunotherapy for MIBC, including tumor mutation burden (TMB), a DNA damage response (DDR) 9-gene panel (NCT03609216) associated with response to neoadjuvant chemotherapy, and an 8-gene cytotoxic T cell transcriptional signature associated with response to neoadjuvant A (tGE8; Powles et al, Nature Medicine 2019). We also evaluated TGF-β pathway activation, which was associated with resistance to A in pts with metastatic BC (Mariathasan et al, Nature 2018). Putative biomarkers were assessed for correlation with &lt; pT2N0, the trial’s primary endpoint. Results: DNA was available from all 36 pts, and RNA met quality control metrics for 29 pts. TMB was significantly higher in pts with &lt; pT2N0 (median 16 mut/Mb, IQR 12-25) versus ≥ pT2N0 (median 10 mut/ Mb, IQR 8-10; p &lt; 0.01). A single patient had a TMB &gt; 200 Mut/Mb with a POLE hotspot mutation and achieved pT0N0; TMB was still significantly higher in responders after omission of this patient (p &lt; 0.01). Nine of 25 pts (36%) with &lt; pT2N0 had a deleterious DDR mutation versus 1 of 10 pts (10%) with ≥ pT2N0 (p = 0.13). While tGE8 was significantly increased in patients with &lt; pT2N0 compared to those without (p = 0.01), TGF-β pathway activation was not increased in pts with ≥ pT2N0 (p = 0.99). Conclusions: TMB and the tGE8 cytotoxic T cell transcriptional signature were associated with response to combination GC+A in muscle-invasive bladder cancer. More detailed molecular analyses will be reported. Clinical trial information: NCT02989584.
An open-label, non-randomized, multi-center phase I study evaluating the safety, tolerability, pharmacokinetics and preliminary efficacy of bi-ligand-drug conjugate CBP-1018 in patients with advanced solid tumors.
Authors: Kaiwen Li, Yehui Shi, Junyan Wu, Liyan Zhou, Suiwen Ye, Xiuping Lai, Robert Huang, Yan Teng, Jiangang Yu, Xiaoyan Chai, Hai Huang
Journal: Journal of Clinical Oncology (2022)

TPS2694 Background: Folate-receptor 1 (FOLR1) and prostate specific membrane antigen (PSMA) are overexpressed on tumor and angiogenic endothelial cells in solid tumors, including prostate cancer, renal cell cancer and lung cancer. CBP-1018 is a first-in-class bi-ligand drug conjugate targeting to both FOLR1 and PSMA, with a tubulin inhibitor payload, monomethyl auristatin E (MMAE). We herein introduce its first-in-human study which is designed based on the significant anti-tumor potency and acceptable safety profile in nonclinical studies. Methods: This study is a phase Ⅰa/Ⅰb, multicenter, open-label study enrolling patients with advanced solid tumor relapsed after previous standard therapies. The primary objective is to assess CBP-1018 safety, tolerability, dose limiting toxicity and maximum tolerated dose. Preliminary efficacy including objective response rate, duration of response and progression-free survival will be observed. Pharmacokinetics, immunogenicity and biomarkers will be also evaluated. This study includes 2 parts: Ⅰa (Dose Escalation) and Ⅰb (Dose Expansion). CBP-1018 is administrated iv Q2W (4 weeks/cycle) in Ⅰa, with accelerated titration at lower doses (0.03 mg/kg and 0.06 mg/kg) and an i3+3 design at following doses (0.08 mg/kg, 0.10 mg/kg, 0.12 mg/kg and 0.14mg/kg, etc.). Subjects will be enrolled in 4 cohorts in Ⅰb: metastatic castration resistant prostate cancer, advanced renal cell cancer, advanced lung squamous cell cancer, and other advanced solid tumors. Efficacy will be assessed every 8 weeks (±7days) according to RECIST 1.1, PCWG3 and PSA assessment (only for prostate cancer). Treatment will be continued untill disease progression or intolerable toxicity. Enrollment has been started in Nov. 2021 and is ongoing. Clinical trial information: NCT04928612.
Circulating tumor DNA (ctDNA) in HER2 exon 20 insertion mutations and responses in NSCLC HER2 exon 20 insertion treated with poziotinib.
Authors: Arunthi Thiagalingam, Sribalaji Lakshmikanthan, Allysia Mak, Scott A. Shell, Sharon Leu, Sophie Sun, Erin Marie Bertino, Eric B. Haura, Rocky Washington, Gajanan Bhat, Francois M. Lebel, John A. Barrett
Journal: Journal of Clinical Oncology (2022)

3051 Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360 â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.
STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.
Authors: Benoist Chibaudel, Louis-Marie Dourthe, Thierry Andre, Julie Henriques, Vincent Bourgeois, Pierre-Luc Etienne, Jérôme Desrame, Elisabeth Carola, Olivier Dupuis, Nabil Baba-Hamed, Dominique Auby, Christophe Louvet, Emmanuel Maillard, Olivier Romano, Christophe Tournigand, Marie-Line Garcia-Larnicol, Einat Shacham Shmueli, Brian Healey Bird, François Ghiringhelli, Aimery De Gramont
Journal: Journal of Clinical Oncology (2022)

3504 Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B &gt; arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]
Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.
Authors: Rasaq Akinsola, Hayato Muranaka, Andrew Eugene Hendifar, Arsen Osipov, Natalie Moshayedi, Shant Thomassian, Aleksandr Stotland, Sarah Parker, Jennifer Van Eyk, Suzanne Devkota, Neil Bhowmick, Jun Gong
Journal: Journal of Clinical Oncology (2022)

e16291 Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change &lt; 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p &lt; 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p &lt; 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p &lt; 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p &lt; 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.
Generating meaningful peer-to-peer engagement through a mentor-led, small group social learning experience on the evolving standards of care for advanced HER2+ breast cancer.
Authors: Latha Shivakumar, Rukiya Wongus, Steven Haimowitz, Lisa Shah, Amanda Ye, Leigh Boehmer
Journal: Journal of Clinical Oncology (2022)

11040 Background: Although the COVID-19 pandemic quickly created a spotlight on distance learning, identifying models that can deliver effective educational programs and best serve the needs of oncology clinicians remains a significant challenge. Methods: We conducted an educational program on the evolving standards of care for advanced HER2+ breast cancer hosted on a novel digital platform that offers a personalized social learning experience which prioritizes engagement, peer-to-peer learning, and mentorship within a small group setting. Results: 87 learners within 10 groups of professionally-connected clinicians participated. Learners progressed through foundational self-study modules, collaborated on asynchronous group challenges, and participated in synchronous live group discussions over six weeks (approximately 4 hours total). Quantitative and qualitative analysis of data extracted from these components highlights the impact of this program (Table). Notably, the learner population was more specialized and engaged than could be expected of a traditional CME program. Feedback suggests strong impact of the live group discussions on learners’ intended practice changes. Additionally, analysis of group challenges and live group discussions revealed several key insights into learner thinking about treatment guidelines, including their differing opinions about the role of surgery/radiation in patient care, uncertainty about the mechanisms of action (MOAs) of discussed therapies, and their apprehension about implementing therapies that may impact the heart and lungs. Conclusions: The outcomes from this analysis highlight the utility of this type of social learning platform to create a safe, supportive learning environment that encourages multiple real-time and asynchronous interactions and shared experiences between clinicians who treat patients with advanced HER2+ breast cancer, as well as offering unique and convenient mentoring opportunities for clinicians interested in leading these digital small groups. Program impact.[Table: see text]
A phase 2 study of anti-PD-L1 antibody (atezolizumab) in grade 2 and 3 chondrosarcoma.
Authors: Mohamad Adham Salkeni, Anthony Paul Conley, James Lin Chen, Elizabeth J. Davis, Melissa Amber Burgess, Albiruni Ryan Abdul Razak, Nancy Moore, Katherine V. Ferry-Galow, Kristin K. Fino, King Leung Fung, Ralph E. Parchment, Jared C. Foster, Christina Rosenberger, Geraldine Helen O'Sullivan Coyne, Naoko Takebe, Elad Sharon, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2022)

11528 Background: Chondrosarcoma is one of the most common bone malignancies in adults, and the third most common in pediatric patients (pts). The most prevalent subtype, conventional chondrosarcoma, is a slow growing tumor that is historically known to be refractory to chemotherapy. Anecdotal reports indicated a role for anti-PD-(L)1 in the treatment of this disease. This is the first prospective report on the efficacy of the PD-L1-targeting agent, atezolizumab, in this rare disease. Methods: Patients (pts) ages 2 and older with unresectable grade 2 or 3 conventional chondrosarcoma were eligible. No prior anti-PD-(L)1 treatment was allowed, otherwise pts were eligible irrespective of prior therapies as long as protocol-specified washout period requirements were met. Pts received atezolizumab 1200 mg (15 mg/kg with 1200 mg cap in pediatric pts) once every 21 days. Imaging was carried out at end of cycle 3, and then every two cycles. Research biopsies were collected from adult pts prior to C1D1, prior to C3D1, and at progression. Immuno-pharmacodynamic (IO-PD) studies were performed on paired tumor samples and circulating immune cells to help elucidate signaling pathways mediating the immune response, with focus on subsets of effector cells in the tumor microenvironment. Results: A total of 9 pts (7 males, 2 females) were enrolled in 6 centers across the US and Canada. Six pts were Caucasian/White, 1 Asian, 1 Hispanic, and 1 unknown. Median age was 49 years (42-72). No objective responses were seen. Three pts (33%) experienced disease stability (SD) per RECIST 1.1, for a median duration of 21 weeks as of data cutoff (January 2022). A patient with SD remains on active treatment (tx) for 35 weeks. Three patients had no tx-related adverse events (AEs). Six pts (67%) experienced at least one tx-related AE. Two patients experienced &gt; G2 AEs, but only one was considered tx-related (lymphopenia). Immune-related AEs were all G1/2 and included hepatitis (2), hypothyroidism (1), hyperthyroidism (1), and maculopapular rash (1). IO-PD studies are ongoing and will be reported at the conference if available. Conclusions: Atezolizumab was well-tolerated but demonstrated limited activity in this cohort of pts with few treatment options. Ongoing IO-PD studies will provide insight into atezolizumab’s effect upon immune cell content and activation in the tumor microenvironment that will help design future immunotherapy trials in this disease and other sarcoma types. The study was funded by NCI Contract HHSN261201500003I. Clinical trial information: NCT04458922.
The combination of the IAP antagonist, tolinapant and hypomethylating agents (HMA) is highly synergistic in <i>in vitro</i> models of T-cell lymphoma (TCL).
Authors: John Manavalan, Ipsita Pal, Aidan Pursley, George Ward, Tomoko Smyth, Martin Sims, David Feith, Thomas Loughran, Owen O’Connor, Enrica Marchi
Journal: Journal of Clinical Oncology (2022)

e15088 Background: Peripheral T-cell lymphoma (PTCL) are a highly aggressive and heterogeneous group of non-Hodgkin lymphomas that often carry a poor prognosis with standard chemotherapy. Tolinapant is a potent antagonist of inhibitors of apoptosis proteins (cIAP1/2 and XIAP). In a phase 2 trial (NCT02503423), tolinapant showed activity against heavily pre-treated patients with TCL. We explored the sensitivity of a range of TCL lines to tolinapant, established the synergy coefficient and interrogated the mechanism of synergy between tolinapant and drugs active against PTCL including romidepsin, pralatrexate, and the HMAs; azacytidine and decitabine. Methods: A panel of 10 human TCL lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10 ng/ml of TNFα. For combination studies, each drug was tested, in the presence or absence of TNFα. Synergy coefficient was calculated using Excess over Bliss. Additionally, the on-target effects of the drugs were measured by analyzing levels of the IAPs, acetylated histones, DNMTs and key apoptosis and necroptosis markers by Western blotting. Results: TCL Lines demonstrated varying sensitivities to tolinapant with the most sensitive cell line, ALK+ ALCL SUP-M2, having an IC 50 as low as 20 nM ± 1 nM while a resistant CTCL cell line HH had an IC 50 of over 20 µM. In combination experiments using both cell lines, tolinapant plus azacytidine or decitabine displayed the highest degree of synergism, compared to romidepsin or pralatrexate. Of note, a high degree of synergism was also seen with concentrations 10 folds lower of azacytidine or 100 folds lower of decitabine, added daily (Table). The combination of tolinapant and the HMAs led to a decrease in the levels of cIAP1 and DNMT3a in TCL lines, demonstrating on-target activity of tolinapant and the HMAs, respectively. In addition, both azacytidine and decitabine increased the levels of RIPK3 and MLKL by western blot analysis, indicating activation of the necroptosis pathway. Conclusions: Tolinapant has demonstrated varying cytotoxic effects against a range of TCL lines as a monotherapy and displays a very high degree of synergism in combination with the HMAs, azacytidine and decitabine, also at low concentration, in vitro. The HMAs were also able to activate the necroptosis pathway, providing a possible mechanism for the high degree of synergism displayed when combined with tolinapant in the TCL lines in vitro. These data provide the rationale to initiate phase I trials with the combination of tolinapant and HMAs. Average synergy scores at 48 hrs for drugs used in combination with tolinapant in a CTCL line HH and ALK+ ALCL line SUP-M2. Above 10 indicates synergy.[Table: see text]